Magnetic nanoparticles have been extensively studied. D. L. Leslie-Pelecky and R. D. Rieke, Chem. Mater., 1996, 8, 1770. They are known to change their magnetic properties from ferromagnetic to superparamagnetic below a critical size. Ultrafine particles of magnetic oxides may be used for preparing liquid magnets or ferrofluids. M. Saynattjoki and K. Holmberg, Synthetic Lubrication, 1993, 10, 119; T. Hemmi, Japanese Journal of Tribology, 1992, 37, 155. Generally, the particles are dispersed in water or non-polar solvents (hydrocarbons). Because they are used in numerous types of devices requiring liquid flows, the dispersions need to have high stability with respect to agglomeration and sedimentation in order to be able to flow and to respond quickly and without magnetic hysteresis to the imposition of an external magnetic field. D. L. Leslie-Pelecky and R. D. Rieke, Chem. Mater., 1996, 8, 1770; M. Saynattjoki and K. Holmberg, Synthetic Lubrication, 1993, 10, 119; T. Hemmi, Japanese Journal of Tribology, 1992, 37, 155; U.S. Pat. No. 5,147,573; U.S. Pat. No. 4,094,804; U.S. Pat. No. 3,764,540; U.S. Pat. No. 3,843,540.
Various techniques for preparing particles in solution are known in the art. The synthesis procedures in aqueous solution show difficulties in the control of the particle size and size distribution, as well as the methods of prolonged milling. Other techniques, such as gas evaporation or sputtering, require complex equipment and are plagued by their high costs. The drawback of the methods commonly used is the poor particle dimensional control, both in size and size distribution. In particular, aggregation phenomena can occur in these processes.
Magnetic nanoparticles provide for required colloidal stability in aqueous environments and are of special interest because of their important technological applications in disparate fields ranging from magnetic recording to bio-diagnostics and therapeutics. Surfactant-coated magnetic nanoparticles of metal oxide have been reported. A. Ulman, R. P. Scaringe, Langmuir, 1992, 8, 894. Works describing the synthesis and characterization of self-assembled multiple coatings on nanoparticles is an emerging field important in light of the renewed significance of nanostructured materials and devices. Magnetite stabilization using bilayer coatings has been described by Hatton et al. L. Shen, P. E. Laibinis, T. A. Hatton., J. Magn. Matter., 1999, 194, 37.
Coating of surfaces can often change the intrinsic physical-chemical properties of the nanoparticles. The coatings on the surface of nanostructured powders are of great interest, because the coatings alter the charge, functionality, and reactivity of the surface, and enhance the stability and dispersibility of the nanoparticles in water-prepared monolayer and bilayer surfactant coatings on magnetite (Fe3O4) nanoparticles using the self-assembly method. C. S. Weisbecker, M. V. Merrit, G. M. Whitesides, Langmuir, 1996, 12, 3763; R. G. Nuzzo, B. R. Zegarski, L. H. Dubois, J. Am. Chem. Soc., 1987, 109, 733; C. J. Sandorff, S. Garoff, K. P. Leung Chem. Phys. Lett., 1983, 96, 547; L. Fu, V. P. Dravid, D. L. Johnson, Appl. Surf. Sci., 2001, 181, 173. Reactions between magnetic nanoparticles and various groups via covalent, ionic, coordination, van der Waals, and/or hydrogen bonds are well-known in the art. M. Aoyagi, H. Sato, K. Yagi, N. Fukuda, S. Nishimoto, Colloid & Polymer Science, 2001, 279, 46; Pan, H. K., Meagher, A., Pineri, M., Knapp, G. S., Cooper, S. L. J., Chem. Phys., 1985, 82(3), 1529; Xulu, P. M.; Filipcsei, G.; Zrinyi, M., 2000, 33(5), 1716; Shchukin, D. G., Radtchenko, I. L., Sukhorukov, G. B., J. Phys. Chem. B., 2003; 107(1), 86; Shen, L., Laibinis, P. E., Hatton, T. A., Langmuir, 1999, 15(2), 447; Shen, L., Stachowiak, A., Hatton, T. A., Laibinis, P. E., Langmuir, 2000, 16(25), 9907. The presence of an organic phase can alter both the mass-transfer coefficient and the interfacial area, wherein the interfacial area is enhanced by means of bonding a thin organic, preferably hydrocarbon or polymeric layer, to fine, solid, magnetic nanoparticles. The coated magnetic particles are now capable of solubilizing gases, such as oxygen, and may be used in fermentation processes.
In general, absorption of sparingly soluble gases into a liquid is limited by the rate of mass transfer. This problem impacts, for example, the fields of catalysis (e.g., hydrogenation and oxygenation reactions), bioprocesses (e.g., oxygen transport in aerobic fermentations, oxygenation of blood), and toxic waste gas treatment. For example, in the field of bioprocesses, oxygen transfer poses a limitation to higher cell culture productivities. The use of a microdispersed organic phase into the fermentation broth with an enhanced capacity to solubilize oxygen has been found to alleviate oxygen limitations. M. Elibol, F. Mavituna, Applied Microbiology and Biotechnology, 1995, 43(2), 206; Rols, J., G. Goma, Biotechnology Advances, 1989. 7(1), p. 1–14; and Yamane, T., Yoshida, F., Journal of Fermentation Technology, 1974. 52(7), 445. Use of PFC-coated or hydrocarbon-coated nanoparticles instead of microdispersions, increases the efficiency of such dispersed phases by altering both the mass-transfer coefficient and the interfacial area available for mass transfer.
Methods of preparing fine magnetic particles coated with thin organic layers containing hydrocarbon groups capable of solubilizing gases are known in the art. U.S. Pat. No. 4,867,910 (Meguro, et al. Sep. 19, 1989) discloses ferrofluid compositions wherein an organic layer bearing hydrocarbon groups is bonded to magnetic particles. The organic layer can be selected from the group consisting of anionic surfactants having at least one polar group and wherein the anionic surfactant has at least 10 carbon atoms, and nonionic surfactants, e.g., an unsaturated fatty acid such as an oleic acid or a salt thereof, a petroleum sulfonate or the salt thereof, a synthetic sulfonate or a salt thereof, polybutene succinic acid or a salt thereof, a polybutene sulfonic acid or a salt thereof, polyoxyethylene nonyl phenyl ether and the like. However, such ferrofluid compositions provide for magnetic particles that are only colloidally stable in organic solvents, and aggregate, precipitate, and sediment in aqueous media such as fermentation broths and the like. Similarly, U.S. Pat. No. 6,780,343 (Hata, et al. Aug. 24, 2004) disclose stably dispersed magnetic viscous fluid wherein a magnetic particle is dispersed in an organic medium by means of bonding of magnetic particle core to a surfactant with a hydrocarbon group of 1 to 22 carbon atoms, preferred examples of the above hydrocarbon group of 1 to 22 carbon atoms includes alkyl groups of 1 to 18 carbon atoms, aryl groups of 6 to 14 carbon atoms, and arylalkyl or alkylaryl groups of 7 to 22 carbon atoms. As the more preferred species, methyl, ethyl, n-butyl, octyl, dodecyl groups and the like were mentioned. Likewise, such magnetic compositions are unstable in aqueous media.
Fine magnetic particles containing hydrocarbon groups that are stable in aqueous media are also known in the art. For example, U.S. Pat. No. 4,094,804 (Shimoiizaka, Jun. 13, 1978) discloses method for preparing a water base magnetic fluid wherein magnetic fluid is provided by adding an unsaturated fatty acid with 18 carbon atoms or a salt thereof into a colloidal solution of a ferromagnetic oxide powder in water, subsequently adding an anionic surfactant with 8 to 30 carbon atoms, or a non-ionic surfactant with 8 to 20 carbon atoms. Each particle of the ferromagnetic powder in the fluid is coated with a monomolecular layer of the ionized unsaturated fatty acid and with the non-ionic or anionic surfactant layer being adsorbed on the first monomolecular layer. However, the adsorption of an non-ionic surfactant upon anionic surfactant or cationic surfactant upon anionic surfactant on the surface of the magnetic particles without chemical or covalent bonding of the surfactants inevitably leads to instability of the resulting doubly-coated magnetic particles. That is, the second coating layer dissociates and desorbs from the first coating layer in the presence of living microorganisms and cells, metal ions and the like ingredients of the fermentation broths, by mass action law. The components of the second coating layer desorbed and dissolved in said fermentation broths are toxic to the living microorganisms and cells and being surface active, cause excessive foaming harmful to the bioprocess.
Fine magnetic particles containing hydrocarbon groups that are stable in aqueous media and wherein the first and second hydrocarbon layers are chemically bonded to each other so that the particles do not release surfactants in water are also known in the art. For example, Shen at al. (Shen, L.; Stachowiak, A.; Hatton, T. A.; Laibinis, P. E.; Langmuir, 2000, 16(25), 9907) discloses magnetic fluids consisting of magnetite nanoparticles and a surrounding bilayer of a primary and a secondary fatty acid surfactant comprising either 10-undecenoic acid or undecanoic acid for one or both of the surrounding layers. The olefin units capable of solubilizing gases were included within the structure as sites for polymerizing the shell components and increasing the stability of the magnetic fluid. Such particles do not release surfactant in aqueous milieu. However, we discovered that due to the unfavorable ionization pattern of the carboxylic groups exposed to the surface of the second olefinic layer, which are responsible for the colloidal stability of the particles, said particles must be exposed to pH above 7.4 and an aqueous medium devoid of significant content of metal ions to remain colloidally stable. Hence, said magnetite nanoparticles stabilized by polymerized fatty acids are disadvantageous in applications involving bioprocesses carried at pH 7.0 and below as well as in the presence of metal ions such as calcium, magnesium, and the like.
Polymer-stabilized magnetic particles, due to their relatively rapid magnetic separation, have been used in biomedical and bioengineering, such as cell separation, immunoassay, and nucleic acids concentration. Y. Haik, V. Pai, C. J., Che J. Magn. Magn. Mater., 1999, 194, 254; K. Sugibayashi, Y. Morimoto, T. Nadai, Y. Kato, Chem. Pharm. Bull, 1977, 25, 3433; M. Mary In: U. Hafeli, W. Schutt and M. Zborowski, Editors, Scientific and Clinical Applications of Magnetic Carriers, Plenum Press, New York (1997), p. 303.; A. Elaissari, M. Rodrigue, F. Meunier, C. Herve, J. Magn. Magn. Mater., 2001, 225, 127. In addition, magnetic polymeric particles offer a high potential in several areas of application, such as detoxification of biological fluids and the magnetic guidance of particle systems for specific drug delivery processes. P. K. Gupta, C. T. Hung, Life Sci., 1989, 44, 175. The hydrophilic magnetic latexes have been reported by Kawaguchi et al. by using acrylamide as the principal monomer. H. Kawaguchi, K. Fujimoto, Y. Nakazawa, M. Sakagawsa, Y. Ariyoshi, M. Shidara, H. Okazaki, Y. Ebisawa, Colloid Surf. A, 1996, 109, 147. Another type of hydrophilic magnetic particles has been reported by Sauzedde et al. using a particle-coagulation methodology. F. Sauzedde, A. Elaissari, C. Pichot, Colloid Polym. Sci., 1999, 277, 846; F. Sauzedde, A. Elaissari, C. Pichot, Colloid Polym. Sci., 1999, 277, 1041; K. Furusawa, K. Nagashima, C. Anzai, Colloid Polym. Sci., 1994, 272, 1104. Hydrophilic thermally sensitive latexes have been obtained by encapsulating adsorbed iron oxide nanoparticles onto oppositely charged polystyrene-core/poly(N-isopropylacrylamide)-shell. The encapsulation has been performed using water-soluble monomers only (N-isopropylacrylamide, N-N′methylene bis-acrylamide and itaconic acid). The final particles exhibit thermal-sensitive property. In addition, various original methods (via non-conventional polymerization) have been investigated using natural polymers or proteins. However, the aforementioned methods in the elaboration of magnetic polymeric latexes lead to submicron particles size (generally above 500 nm) with appreciable iron oxide content.
However, none of the aforementioned research utilized fluorine-containing polymers for the stabilization of magnetic particles. Notwithstanding the fact that fluorinated polymers have a range of remarkable properties including exceptional chemical and biological inertness, and a high oxygen-dissolving capacity. These fluorinated polymers are advantageously used as oxygen carriers in applications such as blood substitutes for oxygen delivery in different clinical settings, as well as for enhancement of bioproduction. R. E. Banks, B. E. Smart, J. C. Tatlow Organofluorine Chemistry, Principles and Commercial Applications, Plenum Press, New York (1994); S. F. Flaim, Biotech., 1994, 22, 1043; M. P. Krafft, J. G. Riess, J. G. Weers, The design and engineering of oxygen-delivering fluorocarbon emulsions. In: S. Benita, Editor, Submicronic Emulsions in Drug Targeting and Delivery, Harwood Academic Publ., Amsterdam (1998), pp. 235–333; G. Riess, M. Le Blanc, Angew. Chem. Int. Ed. Engl., 1978, 17, 621; Dixon, D D, Holland, D G., Fluorocarbons: properties and syntheses, Federation Proceedings, Volume 34, Issue 6, May 1975, Pages 1444–1448; McMillan, J. D., Wang, D. I., Ann NY Acad Sci., 1990, 589:283–300.
U.S. Pat. No. 5,695,901 relates to a method for producing nano-size magnetic iron oxide particles. An iron reactant is contained in a disperse phase, reacted with a basic reactant and subjected to a controlled oxidation by the addition of an oxygen-containing oxidant. Precursor particles are precipitated in droplets of a disperse aqueous phase of the microemulsion. The precursor particles are oxidized in a carefully controlled environment to form the desired magnetic particles and to avoid overoxidation to produce undesirable nonmagnetic particles, such as hematite. However, the presence of oxygen-dissolving fluoropolymers would make such controlled oxidations difficult if not impossible.
U.S. Pat. No. 5,725,802 relates to a process for the preparation of metal oxide particles including magnetic iron oxide particles. Water-in-oil microemulsions are formed in which the oil used is Galden HT70 (a fluorinated oil with high vapour pressure) and the like, and metal ions in the aqueous phase are reacted with a gaseous or vapor reactant. The resulting nanoparticles are coated with perfluoroether, such as phosphoric monoester having perfluoropolyether hydrophobic chain and average MW of approximately 3000 and the like, and are hydrophobic and water-insoluble. Such hydrophobicity and difficulty of separation of the coated nanoparticles from the fluorinated oil emulsion present a hurdle in using the particles in aqueous-based, biological milieu.
U.S. Pat. No. 5,670,088 relates to a method for forming mixed metal oxide particles. A microemulsions is used which includes a perfluoropolyether oil and a perfluoropolyether surfactant. The method further involves mixing one metal in an aqueous phase with a second metal in a perfluoropolyether oil phase. The addition of an alkali solution is accompanied by heating to form the desired oxide. The coated nanoparticles are hydrophobic.
In industrial fermentation technology, the rate of oxygen supply to submerged cultures has often been identified as a limiting factor. This occurs when the oxygen transfer rate from sparged air is less than the cellular oxygen consumption rate, resulting in dissolved oxygen levels below the critical concentration needed to maintain metabolic activity. In conventionally aerated bioreactors, low oxygen solubility (0.28 mmol/dm3 at 20° C.) combined with slow oxygen transfer rates often led to inhibition of growth and have other negative effects on cells.
The absorption rate of oxygen into liquid media used in bioprocesses such as fermentation processes and the like in the presence of a second, dispersed, organic phase can be significantly increased, because of the higher solubility and diffusivity of oxygen in the organic phase. Cho, M. H. and Wang, S. S., Biotechnol. Lett., 1988, 10, 855; Hassan, I. T. M. and Robinson, C. W., 1977, Biotechnol. Bioengng, 1977, 19, 661; Ho, C. S., Ju, L.-K. and Baddour, R. F., Biotechnol. Bioengng, 1990, 36, 1110; Ju, L.-K., Lee, J. F. and Armiger, W. B., Biotechnol. Prog., 1991, 7, 323; Junker, B. H., Wang, D. I. C. and Hatton, T. A., Biotechnol. Bioengng, 1990, 35, 586. The use of an organic phase in a fermentation broth can cause some negative effects on the cell growth and productivity. Nagy, E., Advances in Biochemical Engineering/Biotechnology, 2002, 75, 51. After prolonged contact, the culture system can become unstable due to loss of activity of the microbial cells, toxicity of the oxygen carriers, and/or the increased cell adsorption at the water/oil interface. Chandler, D., Davey, M. R., Lowe, K. C. & Mulligan, B. J., Biotechnol. Letters, 1987, 9, 195; Lowe, K. C., King, A. T. & Mulligan, B. J., Biotechnol., 1989, 7, 1037; Wang, D. I. C., Junker, B. H. & Hatton, T. A., Biotechnol. Bioeng., 1990, 35, 578–585. Covalent attachment of the ultrathin, oxygen-permeable organic layers onto small particles advantageously eliminates direct mixing of the organic liquids with the cells; thus, the toxicity problems related to direct mixing can be avoided.
Without being bound by any theory, the presence of fine solid particles or liquid drops with large oxygen capacity is known in the art to alter the concentration gradient in the liquid boundary layer at the gas-liquid interface and, hence, the gas absorption rate. Alper, E.; Deckwer, W. D., Chem. Eng. Sci., 1981, 36, 1097; Holstvoogd, R. D.; van Swaaij, W. P. M.; van Dierendonck, L. L., Chem. Eng. Sci., 1988, 43, 2181; Demmink J. P.; Mehra, A.; Beenackers, A. A. C. M. Chem. Eng Sci., 1998, 53, 2885; Bruining, W. J.; Joosten, G. E. H.; Beenackers, A. A. C. M.; Hofman, H., Chem. Eng. Sci., 1986, 41, 1873; Rols, J. L.; Condoret, J. S.; Fonade, C.; Goma, G. Biotechnol. Bioeng., 1990, 35, 427; Junker, B. H.; Hatton, T. A.; Wang, D. I. C. Biotechnol. Bioeng., 1990, 35, 578; Junker, B. H.; Wang, D. I. C.; Hatton, T. A. Biotechnol. Bioeng., 1990, 35, 586; Van Ede, C. J.; van Houten, R.; Beenackers, A. A. C. M., Chem. Eng. Sci., 1995, 50, 2911; Chaudhari, R. V.; Jayasree, P.; Gupte, S. P.; Delmas, H., Chem. Eng. Sci., 1997, 52, 4197; Beenackers, A. A. C. M.; Van Swaaij, W. P. M., Chem. Eng. Sci., 1993, 48, 3109.